Show simple item record

dc.contributor.authorBlevins, Sydney J.
dc.contributor.authorPierce, Brian G.
dc.contributor.authorSingh, Nishant K.
dc.contributor.authorRiley, Timothy P.
dc.contributor.authorWang, Yuan
dc.contributor.authorSpear, Timothy T.
dc.contributor.authorNishimura, Michael I.
dc.contributor.authorWeng, Zhiping
dc.contributor.authorBaker, Brian M.
dc.date2022-08-11T08:07:59.000
dc.date.accessioned2022-08-23T15:38:29Z
dc.date.available2022-08-23T15:38:29Z
dc.date.issued2016-03-01
dc.date.submitted2016-07-22
dc.identifier.citation<p>Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1276-85. doi: 10.1073/pnas.1522069113. Epub 2016 Feb 16. <a href="http://dx.doi.org/10.1073/pnas.1522069113">Link to article on publisher's site</a></p>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1522069113
dc.identifier.pmid26884163
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25946
dc.description.abstractHow T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining alphabeta TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the alpha1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Valpha and Vbeta genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26884163&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsPublisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
dc.subjectMHC bias
dc.subjectT-cell receptor
dc.subjectbinding
dc.subjectpeptide/MHC
dc.subjectstructure
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBioinformatics
dc.subjectCells
dc.subjectChemical Actions and Uses
dc.subjectComputational Biology
dc.subjectImmunology and Infectious Disease
dc.subjectInvestigative Techniques
dc.subjectStructural Biology
dc.titleHow structural adaptability exists alongside HLA-A2 bias in the human alphabeta TCR repertoire
dc.typeArticle
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume113
dc.source.issue9
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1093&amp;context=bioinformatics_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/86
dc.identifier.contextkey8870396
refterms.dateFOA2022-08-23T15:38:30Z
html.description.abstract<p>How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining alphabeta TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the alpha1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Valpha and Vbeta genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.</p>
dc.identifier.submissionpathbioinformatics_pubs/86
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.source.pagesE1276-85


Files in this item

Thumbnail
Name:
PNAS_2016_Blevins_E1276_85.pdf
Size:
1.463Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record